Unsaturated-plperazino-alkyl-



States Patent 2,899,431 Patented Aug. ,11, 1959 l 2 2,899,431 ambulatory patient showing mild anxiety or low-grade S A E 1 ERAZINO.ALKYL. tension, the preferred compounds of the invention are PHENQTHIAZINES effective in a dose range of 10 to 250 mg. daily, the aver- Margaret H. Sherlock, Bloomfield, -N.J., assignor to age dose being 9 e emesis, Schering Corporation, Bloomfield, N.J.,.a corporation 5 the compounds of this invention exert adepressant effect of New Jersey at doses of 10 to '15 mg. daily No Drawing. Application September 18,1956 It has been found that, unlike most of the neuropsy- Serial No. 610,659 chiatric drugs in clinical use, the .preferred compounds .of 3 Claims, (CL 260.443) this invention show few untoward side effects. Among 10 the undesirable side effects which are minimized by the This invention relates to a new group of chemical comuse of the compounds of the present invention are dry pounds which possess important therapeutic properties mouth, mydriasis, fall in blood pressure, and tachycardia. and to processes for their manufacture. -My inventi n r By virtue of the lowered 'incidenceof .these side effects, lates to new and useful substituted phenothiazines which the compounds of the invention can be used with relative have therapeutic utility, more specifically, the invention safety in conjunction with barbiturates for preoperative relates to phenothiazyl piperazines which are useful as medicati f d ti ofanxiety chemopsychotherapeutic agents which possess minimal Although all ofsthe compounds of the general formula undesirable side effects. exhibit the aforementioned properties, the strength of Th compounds f my invention are represented by the such properties quite naturally differs in degree between following general formula and include the non-toxic acid 2D structures. For chemopyschotherapeutic application, the addition salts thereof: preferred compounds of the general formula have X representing a'halogen group such as chlorine; A represents S; Y represents an alkylene group containing 3 carbon X atoms and R representsan unsaturated alkyl group. Increasing the number of carbon atoms in Y from 3 to 5 N provides for a decrease in tranquillizing effect, but on the v other hand, the compounds having a longer alkylene chain exhibit more advantageous properties as anti-microbial agents.

Since for the most part, compounds of the general forwherein A is a member of the group consisting of S, 50 mula are insoluble in aqueous media, they'are preferably and S0 X is a member of the'group consisting of H, administered in the form of soluble non-toxic acid addihalogen, lower alkoxy and lower alkyl; Y is an alkylene tion salts such as dihydrochloride, dimaleate, ditartrate, radical of from 2 to 5 carbon atoms; R represents hydrodicitrate and the like. The compounds are preferably adgen or lower alkyl and R" represents an unsaturated hyministered orally in tablets or elixirs in conjunction with drocarbon chain having 3 to 5 carbon atoms. Typical exsuitable carriers and other types of pharmaceutical dosage amples of the group represented by R" are allyl, vpropunits which lend themselves to such administration. In argyl, 2-butenyl, Z-methylallyl and Z-methylbutenyl. certain instances where parenteral administration is indi- I have found that the compounds of the general forcated, the compound in the form of a non-toxic acid addimula possesscertain important physiological properties 40 tion salt is prepared in sterile solutions or suspensions. whichare useful in chemopsychotherapeutic applications. Those compounds possessing anti-microbial properties are These compounds manifest themselves by exerting a-calmpreferably administered topically or locally in the form of ing and a quieting effect, thereby lending themselves to creams, salves and the like application to neuropsychiatric patients in particular. The compounds of my lnventlon may be prepared ac- Thus, in their ability to calm mentally disturbed pacording to a variety-of synthetic steps. Iprefer, however, tients, the restlessness and hyperactivity of the patient are to utilize as starting material the appropriate lO'-('y-chl0- relieved, permitting an improvementin appetiteand-sleepropropylyphenothiazine, for example, 2-chloro-10-(-,1- ing habits. Furthermore, along with their general tranchloropropyl)-phenoth1az ne and react same wlth an apquillizing properties, these compounds areuse'fulinallaypropriately substituted piperazine, for example, 1-allyling anxiety and tension which arise from a myriad of piperazine, and isolating the condensation product so sources, such as gynecologic disorders, dermatologic 'conformed. The condensation may be carried out in the ditions, environmental pressure, premenstrual tension, presence of a condensing agent such as 'sodamlde, potasdysmenorrhea, and menopause. sium amide, metal alcoholates and the like; however, I

In addition to their use in thetreatment of nausea and prefer to employ an excess of the piperazine base to take emesis, some of the compounds possess antihistaminic up the hydrohalic acid produced in the reaction. The properties whereby they allay allergic disorders of local phenothiazyl-alkyl-piperazine is preferentially purified by or systemic nature. Other of the compounds exhibit forrnlng one of 1ts salts which can conveniently be rebroad-spectrum,antifungal properties. crystallized.

:For the schizophrenic or hyperactive neuropsychiatric Instead of employing a plperazlne lntermedlate which patient, it has been found that the preferred compounds is already substituted by an alkenyl group, the compounds of the invention are effective in doses ranging upwards of my invention may be prepared according to the folfrom mg. daily, the average daily clinical dose being lowing equation wherein Phz stands for a 10-phenoth1azyl 200 to 250 mg. depending upon the syndrome. For the group.

H-N N-C O 002E: PhzH Brain-2301 Phz(CH:)aC1 PhZ(CH:)sN NOOOCzH;

NaNH:

1 A1c.KOH i 2) CH CH=CHCOCl LIA-1H It is to be understood from the foregoing reaction that the term lO-phenothiazyl group includes substituted phenothiazines such as 2-chlorophenothiazine, 2-alkoxyphenothiazine and the like.

The compounds of the general formula wherein A represents S or S0 may be prepared by utilizing the appropriate oxygenated phenothiazine as starting material. Compounds of my invention, wherein A of the general formula represents a SO group, are prepared by oxidation of the corresponding compounds wherein A is S, by means of hydrogen peroxide. Although as indicated the oxygenation may be carried out at any stage, I prefer to oxidize at an intermediary stage before the piperazino moiety is incorporated into the molecule. For example, rather than oxygenate 1-allyl-4-.['y-(2-chloro-l0-phenothiazyl)-propyl]piperazine with hydrogen peroxide to yield the corresponding sulphoxy compound, I prefer to treat 2-chloro-10-( -chloropropyl)-phenothiazine with hydrogen peroxide and condense the sulphoxy-phenothiazine so formed with the appropriately substituted piperazine according to the following equation.

CHgCHaGH1Cl HzCHgCH Cl The following examples more clearly describe the preparation of the new compounds of my invention and are given for illustrative purposes only, and my invention is not to be limited thereby except as defined in the appended claims.

EXAMPLE 1 1-allyl-4- ['y-(2-chloro-10-phenothiazyl) propyl] piperazine A mixture of g. of lO-(y-chloropropyl)-2-chloro phenothiazine and 18 g. of l-allylpiperazine is stirred and heated on a steam bath for 18 hours. The reaction mixture is diluted with Water, the oil which separates is extracted with ether. The ether extracts are extracted with dilute hydrochloric acid. The aqueous acid solution is made alkaline with sodium hydroxide solution and the resultant mixture extracted 'with ether. The ether extracts are dried and concentrated to a residue yielding the free base of this example.

This free base is dissolved in 100 ml. of absolute etha- 1101 and a slight excess of ethanolic hydrogen chloride is added. The resulting dihydrochloride separates as White crystals and after filtration is purified by recrystallization a from ethanol; M.P. 248-248.5 C.

By starting with 10-('y-chloropropyl)-phenothiazine in M place of the 2-chloro analog there is obtained, in similar manner, 1-allyl-4- ['y-(10-phenothiazylJ-propyl piperazine.

4 EXAMPLE 2 1 -pr0pargyl-4- ['y- (2-chlor0-1 O-phenothiazyl propyl] piperazine The requisite intermediate l-propargyl-piperazine is prepared as follows: A solution of 86 g. of anhydrous piperazine, 60 g. of propargyl bromide and 60 ml. of absolute ethanol is refluxed for 20 hours. The solvent is removed in vacuo, the residue is dissolved in 200 ml. of water and the solution so formed is saturated with solid potassium carbonate. The resultant mixture is extracted with ether, the extracts are dried, distilled and the fraction boiling at 82-90/7.0 mm. is collected. The substituted piperazine so obtained crystallizes in the receiver; M.P. 53-54.

A mixture of 17.5 g. of l-propargyl-piperazine, 33 g. of lo-(v-chloropropyl)-2-chlorophenothiazine and 14 g. of anhydrous sodium carbonate is stirred and heated on a steam bath for 20 hours. The mixture is diluted with water and the oil which separates is extracted with ether. The combined ether extracts are extracted with dilute hydrochloric acid. The acid solution is made alkaline with sodium hydroxide solution and the resultant mixture is extracted with ether. The ether extracts are dried, concentrated and the residue is converted to the dihydrochloric salt as described in Example 1; M.P. 211212. Analysis indicates that the salt crystallizes with 0.5 mole of water of crystallization.

By condensing l-propargyl-piperazine with 10-(A- chlorobutyl)-2-methoxyphenothiazine in similar manner, there is obtained the dihydrochloride of 1-propargyl-4-[A- (2-methoxyl 0-phenothiazyl) -butyl]piperazine.

EXAMPLE 3 I-(Z-bulenyl)-4-['y-(Z-chl0r0-10-phen0thiazyl)- propyIJ-piperazine The requisite intermediate 1-crotonyl-4-[-,'-(2-chlorol0-phenothiazyl)-propyl]piperazine is prepared as follows: To a solution of 36 g. of 4-['y-(2-chloro-lO-phenothiazyl) propyllpiperazine, B.P. 262-264/1 mm., prepared in a conventional manner from 2-chloro-10-('ychloropropyD-phenothiazine and excess anhydrous piperazine and 300 ml. of anhydrous benzene is added 11 g. of crotonyl chloride. The reaction mixture is stirred and refluxed for 18 hours and extracted with dilute sodium carbonate solution. The benzene layer is dried, concentrated in vacuo and the residue is distilled yielding the crotonyl derivative; B.P. 280285/ 1.0 mm.

A solution of 40 g. of the crotonyl derivative obtained above in 200 ml. of anhydrous ether is added to a suspension of 8 g. of lithium aluminum hydride in 600 ml. of anhydrous ether. The reaction mixture is stirred and refluxed for 10 hours and the excess hydride is destroyed by adding a minimum quantity of water. The lithium and aluminum hydroxides so formed are removed by filtration and the ether solution is concentrated to a residue which is purified by distillation; B.P. 272276/ 1.5 mm.

In the foregoing illustration, by starting with an equivalent quantity of 2-methylpiperazine or 2,5-dimethylpiperazine, there is ultimately obtained l-(2-butenyl-4- -(2-ch1oro-10-phenothiazy1)-propyl]-2(or 3) methylpiperazine, B.P. 275-280/1 mm. or 1-(2-butenyl)-4-['y- (2chloro-10-phenothiazyl) propyl]-2,5 dimethylpiperazine, B.P. 285290/1 mm. The position of the methyl group in the mono methyl piperazine has not been determined.

The free bases so obtained are converted into the dihydrochlorides according to the procedure of Example 1.

EXAMPLE 4 1-(2-methylallyl)-3- ['y-(2-chl0r0-10-phenothiazyl)- propyll-piperazine The requisite intermediate 1-(2-methylally)-piperazine is prepared as follows: To a mixture of 1 mole of l-carbethoxypiperazine, 3 moles of sodium bicarbonate and 300 ml. of 95% ethanol is added 1.2 moles of 3-chlor0 Z-methylpropene and the resultant mixture is stirred and heated at 40-5 C. for '5 hours. The alcohol is removed by distillation and one liter of water is added. Themixture is saturated with potassium carbonate, extracted with ether and the ether extracts are dried an concentrated. The residue is refluxed with 500 ml. of concentrated hydrochloric acid for 40 hours. The resultant solution is concentrated to dryness, the residue dissolved in water, the aqueous solution saturated with potassium bicarbonate and thoroughly extracted with ether. The ether ex tracts are dried, concentrated and the residue obtained therefrom is distilled, yielding l-(2-methylallyl)-piperazine; B.P. 1l51l8/6.5 mm.

A mixture of 31 g. of lO-(y-chloropropyl)-2-chlorophenothiazine and 28 g. of l-(2-methylallyl)-piperazine are stirred and heated on a steam bath for 18 hours. The reaction mixture is processed according to the analogous procedure of Example 1, yielding the free base of this example; B.P. 261-264/ 0.5 mm. The free base so obtained is converted to its dihydrochloride with ethanolic hydrogen chloride as heretofore described, M.P. 238439.

EXAMPLE 1-(3-methyl-2-butenyl) -4-['y-(Z-chl0r0-10phen0thiazyl) propyl] -piperazine The requisite intermediate l-(3-methy1-2-butenyl)piperazine is prepared according to the analogous proce dure of Example 4 whereupon l-carbethoxypiperazine is alkylated with 1-chloro-3-methyl-butene-2 in the presence of sodium bicarbonate with hydrolysis of the carbethoxy group occurring in the presence of hydrochloric acid; B.P. 110ll2/5 mm.

By reacting 31 g. of l'O-( y-chloropropyl)-2-chlorophenothiazine and 31 g. of 1-(3-methyl-2-butenyl)piperazine according to the procedure of Example 1, the free base of this example is obtained as a viscous oil; B.P. 267270/l.0 mm. A

In the foregoing examples conversion of the-free bases to their dihydrochloride salts has been sholwnby way of illustration; other non-toxic salts may be formed in the conventional manner. For example, treating the purified free base in isopropyl acetate solution with two equivalents of maleic acid yields the corresponding dimaleate salts. In similar fashion, salts containing other non-toxic anions are prepared.

EXAMPLE 6 1 -ally-4- fi- (2-chl0ro-1 O-phenothiazyl) -ethyl] -piperazz n'e A EXAMPLE 7 1-allyl4- ['y- (Z-fluoro-l O-phenothiazyl -pr0pyll piperazine The requisite intermediate, 10-('y-chloropropyD-Lfluorophenothiazine is prepared as follows:

To a suspension of sodamide (from 3 grams of sodium) in 300 ml. of liquid ammonia is added 30 grams of Z-fluorophenothiazine. After stirring for one hour, there is added 19 grams of l-bromo-S-chloropropane. The ammonia is allowed to evaporate and the residue is diluted with 200 ml. of water. The mixture is extracted with ether and the ether solution is dried over anhydrous sodium sulfate, filtered and concentrated. The residue consists of crude 10-(y-chloropropyl)-2-fiuorophenothiazine 6 as a viscous oil andis used in the next step without further purification.

A mixture of 15 grams of l-allylpiperazine and 15 grams of crude IO-(y-chloropropyl)-2-fluor0phenothiazinc is heated on a steam bath for 18 hours. The mixture is diluted with 200 ml. of water and extracted with ether. The ether solution is extracted with dilute hydrochloric acid. The aqueous acid solution is made alkaline with sodium hydroxide and the oil which separates is extracted with ether. The ether extracts are dried, concentrated and the residue so obtained is converted to a dihydrochloride according to the procedure described in Example 1.

By substituting 1-bromo-4-chlorobutane for the 1- bromo-3-ch1oropropane in the preparation of the intermediate, there is ultimately obtained by analogous reaction, 1-allyl-4- [A- 2-fluoro- 1 0-phenothiazy) -buty'l] -piperazine which is purified by conversion to its dimaleate salt.

EXAMPLE 8 I -pr0pargyl-4- w- (Z-methyl-10-phenothiazyl -pentyl] piperazine The requisite intermediate 2-methyl-l0-(w-chloropentyl)-phenothiazine is prepared from the reaction of Z-methylphenothiazine and l-bromo-S-chloropentane according to the procedure of Example 7.

From the reaction of 17.5 grams of l-propargyl-piperazine and 35 grams of 10-(w-chlor0pentyl)-2-methylphenothiazine according to the procedure of Example 2, the compound of this example is obtained and is purified by conversion to its dihydrochloride salt.

EXAMPLE 9 1 (2-butenyl) -4- -(2-meth0xy-1 O-phenothiazyl) propyl] -piperazine The requisite intermediate Z-methoxy-lO-(q-chloropropyD-phenothiazine is prepared by substitulting an equivalent quantity of Z-methoxyphenothiazine .for the 2- fiuorophenothiazine in Example 7. Reaction of the intermediate so obtained with l-crotonyl-piperazine followed by reduction with lithium aluminum hydride as described in Example 3 yields the compound of this example. Purification is preferably eifected by conversion to the dihydrochloride salt, followed by recrystallization.

EXAMPLE 10 1 -(2-methylallyl) -3-['y-(3-chl0r0-1 O-phenothiazyl) propyl] -piperazine The requisite intermediate 3-chloro-l0-(y-chloropropyl')-phenothiazine is prepared by reacting 3-chlorophenothiazine with l-br0mo-3-chloropropane as analogously described in Example 7. Reaction of the intermediate so obtained with l-(Z-methylallyl)-piperazine according to the procedure described in'Exarnple 4 yields the free base of this example.

EXAMPLE ll 1-allyl-4- [7- (Z-bromo-IO-phenothiazyl) propyl] -piperazine By substituting an equivalent quantity of lO-(y-chloropropyl)-2-bromophenothiazine (prepared from 2-bromophenothiazine and -l-bromo-3-chloropropane as in Example 7) for the l0( -chloropropyl)-2-chlorophenothiazine employed in Example 1 and following the procedure set forth in said example, there is obtained the above-entitled free base.

EXAMPLE l2 1 -.allyl-4- ['y- 2-chl0r0-5 ,5 -d ioxide-l O-phenothiazyl) propyll-piperazine The requisite intermediate 10- 'y-chloropropyl) -pheno- 'thiazine dioxide is prepared by the alkylation of 23 g. of phenothiazine dioxide with sodamide (from 2.5 g. of

sodium) and 16 g. of l-chloro-B-bromopropane according to the procedure described in Example 7. The crude phenothiazine intermediate thus obtained in condensed with l-allylpiperazine as described in Example 1. The product of this example forms a crystalline dimaleate salt when treated with two equivalents of maleic acid in isopropyl acetate.

EXAMPLE 13 1-allyl-4- y-(2-chloro-5-oxid0-JO-phenothiazyl)- propylJ-piperazine The requisite intermediate Z-chloro-S-oxido-lO-(ychloropropyl)-phenothiazine is prepared by adding 125 ml. of 25% aqueous hydrogen peroxide to a stirred and warmed solution of 34 g. of 2-chloro-10-(y-chloro propyl)-phenothiazine in 1300 ml. of alcohol. The reaction mixture is allowed to stand two days and then poured into water containing a small quantity of hydrochloric acid. The precipitate of Z-ChlOl'O-S-OXidO-l0-(7-Ch101'0- propyl)-phenothiazine is filtered and recrystallized from benzene-petroleum ether, M.P. 106407.

A mixture of 20 g. of the sulfoxide of 2-chloro-10- ('y-chloropropyl)-phenothiazine is heated with 17 g. of l-allylpiperazine as described in Example 1 whereupon the free base of this example is obtained. Purification is efiected by conversion to its dihydrochloride salt.

The foregoing examples illustrate preparation of specific compounds which I consider falling within the scope of my invention. It is apparent that varying the starting material and the choice of reagents, other compounds embraced by the generic formula of my invention may be prepared.

The foregoing examples each have illustrated the preparation of representative compounds of this invention by the common method of alkylating a piperazine with a phenothiazyl alkyl halide. The alternate and equivalent process whereby a phenothiazine is alkylated by a piperazino alkyl halide is also suitable for preparing the compounds of this invention. The examples set forth below illustrate this alternate but equivalent process which is applicable to all of the compounds of the invention and not limited to the specific ones described.

EXAMPLE 14 Alternate preparation of the compound Example 1 The requisite intermediate 1-allyl-4('y-chloropropyl)- piperazine is prepared as follows:

A mixture of 30 g. of l-allylpiperazine and g. of 3- chloropropanol is stirred and heated on a steam bath for 8 hours. The mixture is diluted with Water, saturated with potassium carbonate and extracted with ether. The ether extracts are dried over anhydrous potassium carbonate, concentrated and the residue distilled, yielding the intermediate 1-allyl-4-(' -hydroxypropyl)-piperazine, B.P. l-124/3 mm.

To a solution of 20 g. of the piperazino alkanol obtained above in 200 ml. of anhydrous benzene is added 15 g. of thionyl chloride, maintaining the reaction temperature below 10' during the addition. The reaction mixture is refluxed for four hours, cooled and the hydrochloride so formed is filtered rapidly and washed with benzene. The hydrochloride salt is suspended in 150 ml. of anhydrous toluene. Into the cooled toluene mixture is bubbled anhydrous ammonia gas whereupon ammonium chloride separates and is removed by filtration. The toluene solution of 1-allyl-4-('y-chloropropyl)- piperazine is used in the following step.

To a suspension of sodamide (from 2.5 g. of sodium) in 200 ml. of anhydrous toluene is added 22 g. of 2-chlorophenothiazine. After stirring and refluxing for one hour, the mixture is cooled and the toluene solution of 1-allyl-4-('y-chloropropyl)-piperazine is added dropwise. The reaction mixture i tq luxed and stirred for 8 hours and finally diluted with water. The organic layer is separated and extracted with 200 ml. of 48% hydrobromic acid. The acid layer is separated, refluxed for six hours, cooled and made alkaline with sodium hydroxide solution. The oil which separates is extracted with ether and processed further according to the procedure described in Example 1.

I claim:

1. Compounds consisting of the bases of the following formula and their pharmaceutically acceptable acid addition salts:

X N i, Z

--N N -R wherein A is a member of the group consisting of S, SO, and S0 X is a member of the group consisting of H, halogen, lower alkoxy, lower 'alkyl; Y is an alkylene radical having 2 to 5 carbon atoms; Z is a member of the group consisting of H and lower alkyl and R is an unsaturated aliphatic hydrocarbon radical having less than six carbon atoms.

2. Compounds having the formula:

wherein X is a halogen atom, Y is an alkylene group having 2 to 5 carbon atoms and R is an unsaturated aliphatic hydrocarbon radical having less than six carbon atoms.

3. Compounds having the formula:

N tar rt.

References Cited in the file of this patent UNITED STATES PATENTS 2,766,235 Cusic Oct. 9, 1956 2,787,617 Cusic et a1. Apr. 2, 1957 FOREIGN PATENTS 203,708 Australia Oct. 20, 1955 293/ 55 Union of SouthAfrica Aug. 22, 1955 OTHER REFERENCES Martip pt 541.: Arzn. Forsch, vol. 7, pp. 408-9 (1956). 

1. COMPOUNDS CONSISTING OF THE BASES OF THE FOLLOWING FORMULA AND THEIR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS: 